DESCRIPTION: This initial independent research project will focus on the structure/function relationships in CCR5 and related HIV-1 and SIV co-receptors. The entry of HIV and SIV into CD4+ target cells is initiated by the binding of the viral envelope glycoproteins to cell surface CD4. We and others have demonstrated that chemokine receptors then mediate essential transitory steps leading to viral-to-cell membrane fusion. The CCR5 molecule is the principle co-receptor for M-tropic HIV-1 strains that are most commonly transmitted between individuals. However, the determinants of CCR5 interactions with the HIV-1 envelope glycoproteins remain largely unknown. In Specific Aim 1, we will continue to identify residues in the extracellular loops of CCR5 that are important for HIV-1 and SIV co-receptor activity. Several biological assays will be used to elucidate the role of functionally relevant residues in viral fusion. In Specific Aim 2, we will determine if the functional domains of different HIV-1 and SIV co-receptors share a common structure. In Specific Aim 3, we will determine the binding sites of new anti-CCR5 MAbs and pharmacological agents that inhibit CCR5-mediated fusion and entry. We will then map the extracellular surface of CCR5 by a MAb cross-competition analysis. Together, these studies will identify the elements in CCR5 and related co-receptors that are important for viral fusion and entry, and characterize their spatial distribution on the CCR5 surface. The studies of the targets on CCR5 for MAbs and low molecular weight compounds will facilitate the development of inhibitors of co-receptor function. Our investigations will provide a detailed molecular picture of an essential step in the HIV-1 life cycle, and ways to inhibit it by antiviral agents.